Open AccessIdentification of BLNK and BTK as mediators of rituximab‐induced programmed cell death by CRISPR screens in GCB‐subtype diffuse large B‐cell lymphoma
Author(s) -
Thomsen Emil Aagaard,
Rovsing Anne Bruun,
Anderson Mads Valdemar,
Due Hanne,
Huang Jinrong,
Luo Yonglun,
Dybkær Karen,
Mikkelsen Jacob Giehm
Publication year - 2020
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12753
Subject(s) - bruton's tyrosine kinase , rituximab , biology , cancer research , cd20 , diffuse large b cell lymphoma , b cell , breakpoint cluster region , germinal center , lymphoma , immunology , signal transduction , tyrosine kinase , gene , genetics , antibody
Diffuse large B‐cell lymphoma (DLBCL) is characterized by extensive genetic heterogeneity, and this results in unpredictable responses to the current treatment, R‐CHOP, which consists of a cancer drug combination supplemented with the humanized CD20‐targeting monoclonal antibody rituximab. Despite improvements in the patient response rate through rituximab addition to the treatment plan, up to 40% of DLBCL patients end in a relapsed or refractory state due to inherent or acquired resistance to the regimen. Here, we employ a lentiviral genome‐wide clustered regularly interspaced short palindromic repeats library screening approach to identify genes involved in facilitating the rituximab response in cancerous B cells. Along with the CD20‐encoding MS4A1 gene, we identify genes related to B‐cell receptor (BCR) signaling as mediators of the intracellular signaling response to rituximab. More specifically, the B‐cell linker protein ( BLNK ) and Bruton's tyrosine kinase ( BTK ) genes stand out as pivotal genes in facilitating direct rituximab‐induced apoptosis through mechanisms that occur alongside complement‐dependent cytotoxicity (CDC). Our findings demonstrate that rituximab triggers BCR signaling in a BLNK‐ and BTK‐dependent manner and support the existing notion that intertwined CD20 and BCR signaling pathways in germinal center B‐cell‐like‐subtype DLBCL lead to programmed cell death.